1. Field of the Invention
The present invention relates to the use of a transgenic animal for in vivo monitoring of animal models of human cancers. The transgenic animal is useful for testing potential preventative measures and therapeutic modalities as well as determining causative agents of cancer.
2. Description of the Related Art
The study of the molecular mechanisms of tumorigenesis has been greatly facilitated in recent years by the use of animals able to overexpress or not, at the tissue specific or general level, a variety of genes (germ line modification). However, animal models traditionally have been cumbersome because of the difficulty in quantitating tumor burden and the requirement for either bulk tumor growth or animal survival as end points to evaluate the effect of a potential therapy. Small tumors or tumors in difficult to reach areas can go undiagnosed by palpation and can be refractory to caliper measurements.
Over the years, new imaging methods have been developed to overcome this difficulty. Miniaturized imaging equipment and reporter probes have been developed improving the ability to study animal models of disease. These technologies can be used to continuously monitor in vivo tumour development, the effects of therapeutics on individual populations of cells, or even specific molecules. A variety of non-invasive high-resolution imaging methods are now available for the detection and monitoring of deep-seated cancers, as well as their metastases, in animal models. Among these are positron emission tomography (PET), magnetic resonance imaging (MRI) and computed tomography (CT).
PET is a diagnostic tool for the evaluation of cancer that takes advantage of metabolic imaging. Currently, most of these studies are performed with the glucose analog 18F-FDG, which has been shown to accumulate in high amounts in most tumors. 18F-FDG PET is used in the diagnosis, staging, and posttherapy evaluation of cancer. However PET is regarded as an expensive test, demanding technique that is time consuming and substantial expertise and training with a considerable infrastructure (cyclotron, supporting radiochemistry laboratory space, usually two PET scanners, and a significant number of support staff). Owing to the short-lived nature of positron-labeled radiopharmaceuticals, the distribution of labeled ligands off site from a hospital-based cyclotron is still restricted to 18F-labelled compounds. 18F has a half-life of 110 min, which is just long enough to allow for shipment of 18F-labelled products. These reasons make this method too cumbersome and expensive for analysis of large numbers of animals in an experimental therapy evaluation.
MRI and CT are primarily used to display an animal's internal anatomy. Structural MRI technology was developed from nuclear magnetic resonance. MRI is a noninvasive imaging technique that does not use x-rays (unlike CAT scan). The process involves passing a strong magnetic field through the body. The MRI scanner can detect radiation from certain molecules, which are present in different concentrations in different tissues. The fluid contrast between body structures can then be visualized. A cross-sectional imaging is produced in which there is significant contrast between tissues of interest. MRI is used as an imaging technique because of the very detailed pictures of anatomy that can be achieved. However, even though MRI does not need radioactive isotopes, it does require expensive equipment and time consuming analysis of the data, making it less than adequate for high throughput analysis of animal models.
More recently bioluminescence imaging based on in vivo expression of luciferase, the light-emitting enzyme of the firefly, has been used for non-invasive detection of transplanted tumors and of very specific cancer types. Transplanted tumors are, however, only a partial model of human tumorigenesis because the histology of these tumors does not resemble that of the human disease. Moreover, because these tumor models have not been predictive in preclinical trials, the biology of these tumors may not recapitulate the human disease. Specific bioluminescence tumor models are by its own nature of limited use as a tool for the general study of many different types of cancer in animal models.
Thus, there is a need in the art for a technology that could monitor, as a function of time, different aspects of a whole array of neoplasias (e.g. tumor susceptibility and development, response to drugs or external causative events, etc) in a simple, fast, economical and specific way. The present invention fulfills this long-standing need and desire in the art.